Journal of Biomedical Science最新文献

Background: Ulcerative colitis (UC) is one of the two major types of inflammatory bowel disease (IBD), characterized by inflammation of the colon and rectum. The colorectal epithelium, which covers the mucosal surface, maintains homeostasis by supporting commensal microorganisms in the outer mucus layer. Most colorectal epithelial cells (CECs) are absorptive colonocytes distributed primarily in the upper portion of the crypts. These CECs constitute the front-line barrier that modulates mucosal immunity and facilitates the transfer of immune molecules into the lumen. In patients with UC, CECs undergo both apoptosis and pyroptosis. Apoptosis is a physiological, programmed, caspase-dependent, and tightly regulated form of cell death that eliminates aged and damaged cells. In contrast, pyroptosis is an inflammatory, caspase-dependent form of lytic cell death that occurs in response to harmful stressors and toxins. Pyroptosis in CECs involves a broad array of signaling and effector molecules, many of which serve as measurable biomarkers with diagnostic, prognostic, and therapeutic potential.

Conclusions: Dysregulated colorectal microflora significantly contributes to activating the pyroptotic pathway, initiating an inflammasome- and gasdermin-dependent inflammatory cell death process in UC patients. This review discusses the triggers and pathways of pyroptosis in CECs, evaluates recently identified biomarkers, highlights their potential roles in pyroptosis and as therapeutic targets in managing UC, and candidate compounds that have been shown effective UC therapeutics.

Objectives: This study investigated the impact and related mechanisms of single-nucleotide variants (SNVs) in the HBV pre-S/S region on tumor development, and evaluated the role of antiviral therapy.

Methods: A retrospective analysis was conducted in 104 patients of the gray zone. HCC-associated SNVs were analyzed in baseline samples.

Results: HCC occurred in 15 patients (14.4%) during the median follow-up period of 10.4 years. Genotype B HBV-infected HCC patients had more T53C, A273G, and A529G SNVs and genotype C HBV-infected HCC patients had more T53C, G633A, and A3120G SNVs than HCC-free groups. Antiviral therapy reduced the risk of HCC in patients with HCC-associated SNVs in the gray zone both genotype B or C. Ectopic expression of replication-competent HBV plasmids in Huh7 cells expressing HCC-associated SNVs resulted in greater impairment of mitochondrial dynamics, increased production of reactive oxygen species (ROS), decreased mitochondrial membrane potential, lower ATP production, higher basal calcium levels, and reduced calcium buffering capacity compared to controls or wild-type HBV-expressing cells.

Conclusions: CHB patients in the gray zone remain at risk for HCC owing to both wild-type and HCC-associated HBV SNVs, especially the latter, inducing mitochondrial and metabolic dysfunctions. Antiviral therapy reduces the risk of HCC development in these patients.

Background: Physical differences between acute kidney injury and chronic kidney disease, particularly in matrix stiffness, may influence mesenchymal stem cells to promote either regeneration or fibrosis; however, the underlying mechanisms remain unclear. Here, we investigate the role of paraspeckles and the long non-coding RNA Neat1 in TGF-β1-induced stem cell fate determination.

Methods: Mouse kidney progenitor cells (MKPCs) were cultured on stiff (collagen-coated dishes) and soft (type I collagen gel) matrices and treated with TGF-β1. RNA sequencing and subsequent bioinformatic analyses were performed to identify transcriptional differences between cells on stiff and soft matrices under TGF-β1 stimulation. Western-blotting and qPCR were used to quantify target proteins and RNA levels. Immunofluorescence staining and RNA fluorescence in situ hybridization were conducted to examine the subcellular localization of proteins and RNAs. Loss-of-function and gain-of-function experiments were performed using siRNA, shRNA, pharmacological inhibitors and expression vector.

Results: We found that TGF-β1 induced MKPC differentiation into myofibroblasts on stiff matrices or endothelial-like cells on soft matrices. Matrix stiffness regulated PSPC1 and Neat1 to trigger either TGF-β1-induced transdifferentiation into myofibroblasts or angiogenesis on soft collagen gels. Stiff matrices increased the expression levels of Neat1 and PSPC1, whereas soft matrices reduced their expressions. Knockdown of PSPC1 impaired myofibroblast differentiation on stiff matrices and partially reduced angiogenesis on soft matrices. On stiff matrices, TGF-β1 markedly reduced Neat1 levels, potentially releasing PSPC1 to interact with pSmad2/3 and activate EMT-related gene expression, thereby promoting myofibroblast activation. Furthermore, we identified two mechanosensory pathways that PSPC1 and Neat1 responded to mechanical signals via β1-integrin-YAP and Piezo1 pathways.

Conclusions: This study links mechano-regulation of paraspeckle complex to TGF-β1-induced renal mesenchymal stem cell fate, providing insights into mechanotransduction and nuclear signaling in kidney fibrosis and regeneration.

Monoclonal antibodies (mAbs) represent a major class of therapeutics with widespread clinical applications in oncology, immunology, hematology, neurology and infectious disease. Since the introduction of hybridoma technology in 1975, the field has been advanced by a succession of innovations including chimeric and humanized antibody engineering, phage display, transgenic mouse platforms and high-throughput single B cell isolation. These technological developments have enhanced the specificity, potency and safety of mAbs, resulting in 144 FDA-approved antibody drugs on the market and 1,516 worldwide candidates in clinical development as of August 2025. Engineering breakthroughs have led to new modalities of antibody-based therapeutics, such as antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor T (CAR-T) cell therapies. Each of these modalities has therapeutic utility across multiple disease domains. Recent advances in delivery strategies, notably mRNA-lipid nanoparticles (LNPs) and antibody-directed in vivo CAR-T cell reprogramming, can enable precision therapies while reducing off-target effects and manufacturing complexity. The integration of artificial intelligence (AI) and machine learning (ML), next-generation sequencing (NGS), and structural modeling tools has further accelerated antibody discovery, affinity maturation and immunogenicity prediction, allowing for more efficient and rational antibody design. The advances in antibody technology are reflected in the rapid market growth of antibody-based therapeutics, which had global sales exceeding USD 267 billion in 2024. This review provides a comprehensive update on recent developments in antibody discovery platforms, therapeutic formats and market trends, highlighting emerging strategies that are reshaping the landscape of antibody-based medicine. Furthermore, we discuss clinical translation, regulatory landscapes, and the integration of engineering, biology and informatics. Together, these aspects shape a dynamic and multidisciplinary future for the therapeutic antibody field, which is poised to address unmet clinical needs and global healthcare priorities.

The human liver and pancreas are central to metabolic regulation, with the autonomic nervous system orchestrating processes that maintain glucose homeostasis and respond to dynamic physiological demands-ranging from acute energy mobilization during stress to postprandial glucose uptake and storage. However, visualizing and examining the intricate three-dimensional (3D) neural networks within clinical liver and pancreas specimens remains challenging, as conventional two-dimensional (2D) histological methods cannot fully resolve the spatial complexity of autonomic innervation in the liver and pancreas. This review identifies and discusses key biological and technical factors-including tissue autofluorescence, autolysis, photobleaching, and steatosis-that compromise the reliability of 3D neurohistological analysis of the human liver and pancreas. We also highlight emerging optical and chemical methodologies that enable high- and super-resolution 3D tissue imaging, improving signal fidelity, preserving structural detail, and supporting consistent, reproducible analysis. Ultimately, these advances aim to facilitate precise mapping of human liver and pancreas innervation, offering deeper insight into the neural regulation of nutrient assimilation, glucose utilization, and metabolic homeostasis in both physiological and pathological contexts.

Background: Since the COVID-19 pandemic, there has been a documented rise in the incidence of neurological manifestations among individuals complicated with encephalitis or myelitis. The spectrum of neurological symptoms associated with HCoVs infections is expanding. However, the infection characteristics and pathogenesis of seasonal HCoVs to the central nervous system remain obscure. No pharmacological agents have demonstrated the capacity to specifically and efficaciously mitigate the neurological symptoms induced by HCoVs infections to date.

Methods: We developed human cerebral organoids (HCOs) derived from human induced pluripotent stem cells and established a blood-brain barrier (BBB) HCOs co-culture model. We subjected these models to seasonal human coronavirus (HCoV) infections to investigate the viral characteristics within the central nervous system (CNS). Utilizing RNA sequencing, we conducted a preliminary exploration of the mechanisms underlying virus-induced inflammatory responses in the CNS. Furthermore, we assessed the efficacy of antiviral and anti-inflammatory drugs using the HCO model.

Results: Our results showed that among seasonal coronaviruses, HCoV-OC43 replicates efficiently within the organoids, primarily targeting neurons and astrocytes, and disrupts the barrier function of the BBB. RNA sequencing analysis revealed that HCoV-OC43 infection triggers an inflammatory response through the TNF and NF-κB signaling pathways, leading to cell death, impaired neuronal function, and disrupted interneuron signaling. Interestingly, Bardoxolone methyl (CDDO-Me) demonstrated antiviral effects comparable to remdesivir, reducing both inflammation and cell death.

Conclusions: Conclusively, HCOs infected with HCoV-OC43 offer valuable insights into the pathogenesis of HCoVs in central nervous system (CNS), and might serve as a tool for developing novel therapeutic strategies for HCoVs infections, including COVID-19, especially on exploring treatment candidates.

Dendritic cells (DCs) play a crucial role in the coordination of immune responses and have emerged as a potential target for cancer immunotherapy. However, existing DC-based immunotherapies face several clinical challenges, including suboptimal manipulation strategies, poor cross-presentation, and impaired migration. Besides, the complex tumor milieu drives DCs towards a tolerogenic state, leading to immune evasion and cancer progression. Hence, innovative engineering strategies emerging from a thorough understanding of the genetic and molecular aspects of the factors driving DCs to an immune-compromised status will benefit cancer immunotherapy. Taking advantage of the multiplexing potential of gene editing methods such as CRISPR/Cas9 and viral vectors will ensure multiple genome modifications in DCs that can result in higher migration, cross-presentation, and immune-activating cytokine production in a single manipulation step. Such precise DC modifications with high accuracy require the involvement of nanocarrier formulations with high surface functionalization and targeting potential. In this regard, our review provides a comprehensive summary of critical tumor-induced dysfunctions in DCs and promising genome engineering strategies, highlighting nanocarrier-based approaches to mitigate these challenges.

Background: Cervical cancer (CC) remains a significant global health challenge for women, especially in advanced stages where effective treatments are limited. Current immunotherapies, including PD-1/PD-L1 blockades and adoptive T cell therapies, show limited response rates and durability. Dimethyl fumarate (DMF), an FDA-approved drug for autoimmune diseases, has demonstrated direct antitumor activity in several cancers. However, its influence on anti-tumor immunity and its function in CC remain poorly understood. This study aims to investigate the therapeutic potential of DMF in CC models and elucidate its underlying mechanisms of action.

Methods: CC cell lines and mouse models were treated with DMF. Transcriptomics profiling of cervical cancer cells following DMF treatment were analyzed by RNA-seq and bioinformatic methods. Mitochondrial DNA (mtDNA) release, and cGAS-STING activation were assessed via qPCR, immunofluorescence, immunoblotting and ELISA. CD8⁺ T cell recruitment was analyzed by flow cytometry. Combinatorial therapies (DMF + anti-PD-1/TILs) were tested in syngeneic or patient-derived xenografts (PDX) models.

Results: DMF treatment induces mitochondrial dysfunction in tumor cells, resulting in the release of mtDNA into the cytosol. The cytosolic mtDNA in turn activates the cGAS-STING-TBK1 pathway and type I interferon response, leading to the secretion of CCL5 and CXCL10, thereby enhancing CD8⁺ T cell infiltration. Additionally, DMF exhibits synergistic effect with PD-1 blockade in murine CC model, and can enhance the therapeutic efficacy of adoptively transferred T cells toward CC in patient-derived xenografts model.

Conclusion: This work elucidated that DMF reprograms CC cells to activate the mtDNA-cGAS-STING pathway, fostering a chemokine-rich microenvironment that recruits CD8⁺ T cells. The synergistic effect of DMF and PD-1 blockade or TIL therapy underscores its potential as an immunostimulatory adjuvant. These findings suggest that DMF holds promise as a novel immunotherapeutic strategy for improving clinical outcomes in CC.